Seeing beyond the receptive field in primary visual cortex David Fitzpatrick

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1 438 Seeing beyond the receptive field in primary visual cortex David Fitzpatrick Recent studies on the response properties of neurons in primary visual cortex emphasize the dynamics and the complexities of facilitatory and suppressive interactions between the receptive field center and surrounding areas of visual space. These observations raise new questions about the circuitry responsible for receptive field surround effects and their contribution to visual perception. Addresses Department of Neurobiology, Box 3209, Duke University Medical Center, Durham, NC 27710, USA; Current Opinion in Neurobiology 2000, 10: /00/$ see front matter 2000 Elsevier Science Ltd. All rights reserved. Introduction Defining the limits of the receptive field of a neuron in visual cortex has never been a simple issue; however, a fundamental distinction can be made between the region of visual space in which stimuli evoke spike discharges (the socalled classical receptive field, or receptive field center) and a surrounding region that, although not capable of driving responses, can exert robust suppressive or facilitative effects on the response to the presentation of stimuli in the classical receptive field [1 7]. This distinction has had considerable impact on studies of cortical function because center surround interactions have the potential to explain a variety of psychophysical observations in which context alters stimulus detectability or appearance. For example, facilitatory surround effects have been implicated in processes such as contour integration [5,8] and inhibitory effects have been viewed as the basis for perceptual pop-out, curvature detection, and illusory contours [3,6,9 11]. Moreover, receptive field centers and surrounds are thought to be mediated by different cortical circuits. The properties of the classical receptive field are thought to arise from the cortical column and nearby regions of cortex (within 500 µm), whereas surround effects are the province of long-distance horizontal connections that extend for several millimeters across the cortical surface, and/or feedback connections from extrastriate areas (see [12,13] for reviews). The results of several studies published in the period of review have considerably extended our knowledge of the spatial properties of cortical receptive fields and the underlying circuits. Taken together, they emphasize the dynamic nature of the relationship between the classical receptive field and surrounding regions of visual space. At the same time, they pose new challenges for understanding the neural mechanisms that are responsible for these effects as well as their perceptual significance. Defining the receptive field center Before considering center surround interactions in more detail, it is first necessary to distinguish two different methods that have been used to define the borders of the receptive field center. One approach has been to present a small stimulus, usually a light or dark bar at the appropriate orientation, and to use either stimulus-onset location or movement to delimit the area of visual space that elicits spike discharges above some background level. This approach yields what is generally referred to as a minimum discharge field [14,15]. Another approach is to define the receptive field center as the area of visual space over which increasing the stimulus size elicits a larger response [16 18]. This is often assessed using sine-wave gratings, the length and width of the receptive field being defined by characterizing the smallest stimulus dimensions that produce the maximum discharge rate. In principle, each measure provides useful information about the spatial characteristics of a neuron s receptive field. However, the size of the receptive field center calculated using these two measures can be quite different (see [19 ] for a direct comparison). As nicely illustrated in a recent intracellular study by Bringuier et al. [20 ] (see also [21 ] for a similar account of orientation tuning), the reason for this difference is likely to reside in the iceberg-like spatial profile of a cortical neuron s stimulus sensitivity. The peak sensitivity is found near the center of the receptive field, and sensitivity declines to subthreshold levels as one moves away from the center. The minimum discharge field is a fraction of the region that is capable of eliciting a depolarizing response the peak of the iceberg. Receptive field dimensions based on areal summation will often be larger than those using the minimum discharge measure because they are likely to include regions that are incapable of driving the cell when stimulated in isolation but will augment the rate of response to stimulation of the more sensitive areas of the field. As will become apparent, the use of these two different measures of receptive field size contributes to difficulties in evaluating the findings from different studies. Facilitation beyond the classical receptive field? Evidence that stimuli presented beyond the minimum discharge field have a facilitatory influence over the response to stimulation of the receptive field center has been provided in a number of studies [2,5,22]. The most effective stimuli for eliciting surround facilitation are bars or gratings at the cell s preferred orientation that are placed in the receptive field endzones (i.e. along the collinear axis in visual space). However, the relationship between the facilitatory effects of presenting separate stimuli in the center and surround and a neuron s length summation area has remained a matter of controversy. Some authors have argued that facilitatory surround effects can be explained as the placement of surround stimuli within a cell s length summation area; because these authors regard this as part

2 Seeing beyond the receptive field in primary visual cortex Fitzpatrick 439 of the receptive field center, they conclude that there are no facilitatory inputs from the surround [16,17,23 ]. Other authors, however, have demonstrated that facilitatory effects induced by the presentation of discrete stimuli in the center and the surround can be elicited from regions beyond the length summation area in some cases, regions that produce suppression (endstopping) when long bars are used as stimuli [5]. Two recent studies in macaque striate cortex provide a resolution to this apparent contradiction by demonstrating that the length summation areas of cortical neuron receptive fields are not fixed, but vary as a function of stimulus contrast ([19,24 ]; see also [7] for similar results in cat visual cortex). For many cells, the length tuning curve for high-contrast stimuli plateaus at relatively short stimulus lengths, and these cells often exhibit endstopping to longer-length stimuli. At low contrast values, however, the size of the length summation area is increased by as much as 2 to 4 times that found at high contrast levels and there is no sign of a reduced response to longer stimuli. Thus, the same region of visual space can exert no effect, a facilitatory effect, or a suppressive effect on a cell s response, depending on stimulus contrast. A similar contrast dependence is evident in studies that have probed center surround interactions using multiple discrete stimuli. The type of effect induced by presentation of a collinear stimulus outside the minimum discharge field can often be changed from facilitation to suppression by increasing the contrast of the stimulus in the receptive field center [7,18,25,26,27,28]. Thus, whether one views this behavior as a contrast-dependent change in receptive field size or as contrast dependence of surround effects, a single, contrast-dependent spatial summation mechanism is likely to account for many of the observations with both discrete and continuous stimuli. Why should cortical neurons enlarge their summation area at low contrast levels? Sceniak et al. [24 ] argue that this mechanism may effectively trade resolution for sensitivity, pooling signals to enhance the ability to detect contours under conditions where signals are weak. In a general sense, the changes in receptive field summation properties resemble the changes in the surrounds of retinal ganglion cells under low levels of illumination, where the inhibition evoked from receptive field surrounds is reduced in favor of summation of weak signals [29]. This might suggest that the role of summation in contour detection is limited to lowcontrast stimuli; indeed, the contribution of excitatory summation to contour-integration mechanisms at higher contrast levels has been challenged on several grounds [30 ]. Kapadia et al. [19 ], however, provide evidence that length summation area is also enhanced for the presentation of high-contrast stimuli in the receptive field center when they are surrounded by a complex texture pattern. Furthermore, the strength of surround facilitation to high-contrast stimuli can be enhanced or reduced depending on attentional factors [31 ]. Thus, increased levels of summation may be a more general mechanism that operates whenever the signalto-noise ratio limits contour detection. It seems likely that long-range horizontal connections play a major role in shaping the length summation properties of V1 neurons. The fact that these connections arise from pyramidal neurons, that they preferentially link sites with similar orientation preferences, and that they are elongated along a collinear axis in the map of visual space, is consistent with many of the observed effects [32 34]. However, the mechanism that underlies the contrast-dependent change in summation properties remains unclear. Modeling studies have suggested that the level of drive to the receptive field center determines the sign of the response, favoring inhibition at high levels of activity and facilitation at low levels [35,36]. However, the findings from Sceniak et al. [24 ], in which a difference-of-gaussians receptive field model was used to assess changes in surround facilitation and inhibition, suggest that the result may be explained without a change in the strength of inhibition in other words, by changes in the efficacy of horizontal excitatory inputs alone. Clearly, an intracellular analysis of length summation properties at different contrasts would shed considerable light on this issue [37]. Local connections as a source of inhibitory surround interactions One of the principal reasons for assuming that long-distance horizontal connections are the substrate for receptive field surround effects is that nearby sites in visual cortex were thought to represent overlapping regions of visual space; in order to mediate an effect from surrounding regions of visual space, connections would have to extend some distance (1.5 2 mm on average) across the cortical map. But recent studies in cat visual cortex suggest that our view of cortical topography may need to be revised and that the structure of the visuotopic map may bring cells with non-overlapping receptive fields into close proximity, allowing short-range connections to mediate some types of surround effects [38,39 ]. Evidence that the mapping of visual space is less regular than was previously believed comes from experiments in which the positions of the minimum response fields of individual neurons are compared to the maps of orientation preference [38]. Previous studies using optical imaging techniques have demonstrated that orientation is mapped in a systematic fashion across the cortical surface such that nearby sites prefer similar but slightly shifted orientation values. However, this smooth progression is interrupted periodically by small discontinuities (pinwheel centers or fractures). In these regions, the orientation preference of neurons from nearby sites can differ substantially, often by 90 [40,41]. This comparison demonstrates that recording sites from regions near discontinuities in the orientation map are often associated with jumps in receptive field positions; these jumps are rarely encountered in other parts of the orientation map. As a result of this distortion in

3 440 Sensory systems the mapping of visual space, sites that are separated by less than 300 µm near orientation discontinuities can differ significantly in their response properties, preferring orthogonal orientations presented to non-overlapping regions of visual space. What are the consequences of this organization for the responses of cortical neurons? One possibility is that local connectional patterns are altered such that regions of the map with similar properties are strongly connected, whereas neurons in regions near high-rate-of-change areas are less well connected. Using cross-correlation of spike discharges from pairs of neurons, Das and Gilbert [39 ] provide evidence that this is not the case. Neurons separated by distances of up to 800 µm exhibit a high degree of temporal correlation in their firing patterns, regardless of their location in the cortex. This correlation in firing falls off with distance and does not depend on the orientation preference of the members of the pair (cells with orthogonal preferences are just as likely to be correlated in their firing patterns as those with similar orientation preference). Combined with anatomical evidence for a lack of specificity in local horizontal connections [33,34,42], these results suggest that local connections in layer 2/3 are a source of common input for cells that have diverse receptive field properties. Thus, for neurons that lie near discontinuities in the maps of visual space and orientation, local connections could mediate receptive field surround effects, linking cells with non-overlapping receptive fields and different orientation preferences. This possibility has been tested by exploring the effects of presenting short bars oriented orthogonal to the cell s preferred orientation in the region of visual space that lies just outside the neuron s minimum discharge field. In some neurons, this stimulus configuration is found to suppress the response to stimuli in the receptive field center. Furthermore, the degree of suppression is dependent on the position of the neuron within the cortical map. Flank suppression is most prominent for neurons that are located near map discontinuities, in regions where flank and receptive field center stimulation would be expected to activate nearby populations of cortical neurons. Flank suppression is considerably weaker for neurons located distant from the discontinuities, where flank and receptive field center stimulation would be expected to activate more remote populations of cortical neurons. These differences were evident even though the distance in visual space between the receptive field center and the flank regions was identical for both sets of neurons. Das and Gilbert [39 ] suggest that these suppressive interactions support the detection of angles or T-junctions in the visual field and that the machinery to map these more complex stimulus configurations may also be systematically mapped across the cortical surface. In this view, pinwheel singularities are not epiphenoma of the mapping of orientation preference in the cortex, but are a structural arrangement that allows for the analysis of junctional borders. Challenges to the T-junction proposal These are novel and appealing ideas that relate the fine structure of functional maps to receptive field properties and patterns of connectivity. However, additional studies are necessary to confirm the correlation between rate of change in orientation and rate of change in receptive field position that is central to this hypothesis. For example, a recent study that used tetrode recordings to evaluate the fine structure of the mapping of visual space in cat visual cortex did not find a correlation; however, this study did not specifically target regions where orientation preference values are changing rapidly and this could account for the difference [43 ]. Also, analysis of the map of visual space in the tree shrew, using imaging and electrode recordings, indicates that the mapping of visual space is smooth and continuous throughout, showing no sign of jumps that could correlate with orientation pinwheel centers [44]. Likewise, the V1 V2 border region of the ferret, where there are large jumps in the mapping of visual space, is not associated with an increase in the density of pinwheels or fractures in the orientation map [45,46]. Thus, the relationship between the mapping of visual space and the mapping of orientation preference described in the cat is not universal; it remains to be seen whether discontinuities in the mapping of visual space are present in other species, including primates. The relation of these findings to other accounts of the orientation tuning and spatial distribution of inhibitory inputs is also far from clear. Previous studies of inhibitory surround effects have demonstrated that iso-orientation stimuli are far more effective at suppressing responses than orthogonal ones [3,17,22,23,47]. There is, however, evidence that orthogonal stimuli evoke inhibition within the receptive field center, using the areal summation measure as the basis for defining the extent of the center [16,48,49]. This so-called cross-orientation inhibition has been revealed in extracellular recordings by superimposing within the receptive field a grating of the preferred orientation with one of the orthogonal orientation. In these experiments, the most robust suppressive effects are found when the contrast of the grating at the preferred orientation is roughly half that of the orthogonal grating; the same characteristics apply to the flank suppression described by Das and Gilbert [39 ]. More details about the orientation tuning and the spatial distribution of the flanking suppression are necessary to fully compare the two effects; however, if they are the same phenomenon, then there is reason to question whether the flank suppression described by Das and Gilbert has the strict spatial organization or the tight orientation tuning that would be required to serve as a T-junction detector. Receptive field center suppression, at least, is broadly tuned for orientation, a factor that has led to the view that it plays a role in normalizing cortical cell responses, maintaining selectivity of response despite changes in stimulus contrast [16,48,50]. Asymmetric surround suppression Despite the inconsistencies described above, the more general point that inhibitory surrounds are often localized to

4 Seeing beyond the receptive field in primary visual cortex Fitzpatrick 441 small regions of space and can be quite varied in their position relative to the receptive field center finds support in another study of cat visual cortex in which small patches of gratings are used to evaluate the spatial layout of iso-orientation inhibitory flanks [23 ]. On the basis of previous studies using relatively large surround stimuli, iso-orientation inhibitory flanks are conceived as being symmetrical in their distribution around the receptive field, localized either in the end-zones (the source of end-stopping) or along the sides (side-band inhibition). This new analysis demonstrates that inhibitory flanks beyond the excitatory summation zone are more often asymmetric, restricted to one end of the receptive field or to one side. Furthermore, some cells exhibit a single inhibitory flank that is located at an oblique angle to the field in other words, neither at the ends nor at the sides. The functional significance of this array of spatial relationships is not clear; however, it emphasizes that the nature of inhibitory surround interactions is far more intricate and diverse than had been appreciated. The source of suppressive effects Ultimately, the final common path for the expression of these inhibitory effects is the population of smooth-dendritic GABAergic interneurons. This is an extremely diverse class of neurons that differ in their morphology, peptide content, and synaptic properties [51,52]. Although most of these neurons have rather restricted axon arbors, one class, the basket cell, gives rise to axons that can spread upwards of 1.5 mm across the cortical surface [53]. Comparison of the distribution of the axon terminals of this cell class with maps of orientation preference reveals that they contact sites with a broad range of orientation preferences [42]; this suggests that they could be the source of the broadly tuned inhibition that characterizes the receptive field center suppression. However, the isoorientation suppression from the surround is likely to involve excitatory long-distance horizontal connections that synapse with a population of local inhibitory neurons. Although injections of tracer substances generally show a broad distribution of horizontal inputs [32 34], individual neurons may sample selectively from this array to generate the restricted and variable position of the inhibitory flanks. Conclusions The division between the receptive field center and surround continues to provide a framework for understanding how the information from multiple stimuli is encoded in the responses of individual neurons. As recent studies emphasize, however, the distinction between center and surround is less rigid than was once thought. The area of visual space that evokes spike discharges in a neuron is surrounded by a large subthreshold region capable of eliciting depolarizing responses. Consistent with this observation, the size of the spike discharge zone is not fixed but can vary with contrast and context and can be altered by attentional factors. Likewise, the strict linkage between horizontal connections and receptive field surround effects has to be tempered with the evidence for irregularity in the mapping of visual space. Ultimately, elucidating the mechanisms that underlie spatial interactions in visual processing will require techniques that relate the responses of individual neurons to large-scale patterns of activity in the cortical network [54,55,56 ]. In this light, the availability of new voltage-sensitive dye techniques for visualizing cortical activity patterns with high temporal and spatial resolution [57 ] may provide the next step in understanding the significance of the complex array of excitatory and inhibitory interactions that occur within and beyond the receptive field. Acknowledgements Thanks to Frank Sengpiel, Michele Pucak, and Heather Chisum for helpful comments on the manuscript. Support provided by National Institutes of Health grants EY06821, EY06729, and the McKnight Foundation. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. Hubel DH, Wiesel TN: Binocular interaction in striate cortex of kittens reared with artificial squint. J Neurophysiol 1965, 28: Maffei L, Fiorentini A: The unresponsive regions of visual cortical receptive fields. 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5 442 Sensory systems 18. Levitt JB, Lund JS: Contrast dependence of contextual effects in primate visual cortex. Nature 1997, 387: Kapadia MK, Westheimer G, Gilbert CD: Dynamics of spatial summation in primary visual cortex of alert monkeys. Proc Natl Acad Sci USA 1999, 96: This paper demonstrates that the length summation area of receptive fields in primary visual cortex of awake macaque monkeys is dependent on stimulus contrast. On average, the length of the excitatory receptive field is found to be four-fold greater for a low-contrast stimulus than for a stimulus at high contrast. The results also show similar effects when high-contrast stimuli are embedded in a textured background. 20. Bringuier V, Chavane F, Glaeser L, Fregnac Y: Horizontal propagation of visual activity in the synaptic integration field of area 17 neurons. Science 1999, 283: This paper uses intracellular recordings in cat area 17 to examine the spatial distribution of subthreshold excitatory and inhibitory inputs. The authors demonstrate a large visually evoked subthreshold depolarizing field that extends over a much broader area than the minimum discharge field. 21. Carandini M, Ferster D: Membrane potential and firing rate in cat primary visual cortex. J Neurosci 2000, 20: Using intracellular recordings, the authors demonstrate that spike threshold contributes substantially to the sharpening of orientation- and directiontuned responses of cortical neurons, creating a strong iceberg effect. 22. Nelson JI, Frost BJ: Intracortical facilitation among co-oriented, coaxially aligned simple cells in cat striate cortex. Exp Brain Res 1985, 61: Walker GA, Ohzawa I, Freeman RD: Asymmetric suppression outside the classical receptive field of the visual cortex. J Neurosci 1999, 19: The authors provide a detailed account of the spatial distribution and orientation tuning of inhibitory zones that lie beyond the receptive field excitatory summation zone in area 17 of the cat. In contrast to the traditional view of symmetrical end- or side-suppression, the authors show that for most cells suppression is asymmetric, originating from a single localized region. 24. Sceniak MP, Ringach DL, Hawken MJ, Shapley R: Contrast s effect on spatial summation by macaque V1 neurons. Nat Neurosci 1999, 2: This paper demonstrates that the extent of spatial summation depends on stimulus contrast; on average, receptive field extent is 2.3-fold greater at low contrast than at high contrast. Using a difference-of-gaussians model, the authors provide evidence that this increase in spatial summation is attributable to alterations in the spread of excitation independent of surround suppression. 25. 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6 Seeing beyond the receptive field in primary visual cortex Fitzpatrick Gupta A, Wang Y, Markram H: Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. Science 2000, 287: Based on an impressive number of simultaneous patch recordings from GABAergic interneurons and their postsynaptic targets in rat cortical slices, the authors provide evidence for 14 different classes of interneurons, on the basis of discharge pattern and axonal tree morphology. Furthermore, these 14 classes sort into three functional groups that differ in their response to repetitive stimulation. 52. Miles R: Diversity in inhibition. Science 2000, 287: Kisvarday ZF, Eysel UT: Cellular organization of reciprocal patchy networks in layer III of cat visual cortex (area 17). Neuroscience 1992, 46: Grinvald A, Lieke EE, Frostig RD, Hildesheim R: Cortical pointspread function and long-range lateral interactions revealed by real-time optical imaging of macaque monkey primary visual cortex. J Neurosci 1994, 14: Jancke D, Erlhagen W, Dinse HR, Akhavan AC, Giese M, Steinhage A, Schoner G: Parametric population representation of retinal location: neuronal interaction dynamics in cat primary visual cortex. J Neurosci 1999, 19: Using the responses of neurons in cat visual cortex to the presentation of small squares of light, the authors construct distributions of population activity for each stimulus and then compare the response to individual stimuli with that to two stimuli at varied separations. The results provide evidence for a non-linear distance-dependent repulsive effect that results from the spatiotemporal spread of excitation and inhibition. 56. Tsodyks M, Kenet T, Grinvald A, Arieli A: Linking spontaneous activity of single cortical neurons and the underlying functional architecture. Science 1999, 286: By combining real-time voltage-sensitive dye imaging with extracellular recordings from individual neurons, the authors demonstrate that the spontaneous activity of single neurons reflects the instantaneous spatial pattern of activity in a large cortical area and that this pattern is similar to that seen when neurons are activated by visual stimuli. The results emphasize the extent of, and the specificity in, the distributed activity patterns of cortical circuits factors that are likely to play a significant role in the excitatory and inhibitory spatial interactions that constitute receptive field surround effects. 57. Shoham D, Glaser DE, Arieli A, Kenet T, Wijnbergen C, Toledo Y, Hildesheim R, Grinvald A: Imaging cortical dynamics at high spatial and temporal resolution with novel blue voltage-sensitive dyes. Neuron 1999, 24: An excellent review of the advances in in vivo voltage-sensitive dye recordings that allow the visualization of large-scale patterns of cortical activity.